Diabetic foot ulceration (DFU) is a major problem that significantly impairs the quality of life of the patient, leads to prolonged hospitalization and may require a major amputation. Previous work from our unit has shown that there is reduction in skin blood flow and oxygenation and reduced energy reserves of the foot muscles in diabetes. The main hypothesis for this study is that these abnormalities in the skin microcirculation and muscle metabolism are responsible for the failure to heal plantar diabetic foot ulcers. In addition, we hypothesize that the rate of wound healing is associated with the number of circulating endothelial progenitor cells (EPCs). In order to explore our hypotheses, we plan to follow up diabetic patients with plantar foot ulceration for a 12-week period. It is estimated that 35%-45% of this population will achieve complete wound healing during this period. 1 group of diabetic patients at low risk of foot ulceration and a group of healthy control subjects will also be enrolled so comparisons with the group with foot ulceration can be made. We will evaluate skin microcirculation vascular reactivity, localized tissue oxygen delivery and oxygen extraction, using Medical Hyperspectral Imaging (MHSI) and circulating Endothelial Progenitor Cells (EPCs) at baseline, 4, 8, and 12 weeks and foot muscle metabolism, using a 3T MRI RARE technique, at 0 and 12 weeks. We hypothesize that hyperspectral tissue oxygen saturation (SHSIO2), muscle metabolism and circulating EPCs will be reduced in the diabetic patients at risk of foot ulceration and that this reduction will be more pronounced in the patients who fail to heal their ulcers. We further hypothesize that the increase in oxygen delivery and oxygen extraction related to the angiogenic response required for wound healing will be less prominently observed in those patients who do not heal their ulcers. We believe that this proposal includes interdisciplinary, translational and clinical components that will increase our knowledge in a very important field and will help us to better understand the pathophysiology of wound healing in DFU. We also believe that the accumulation of such knowledge will pave the way to the development of new therapeutic strategies that will greatly enhance our efficacy in managing this condition. In addition, we believe that it will be helpful in understanding the relationship between cardiovascular disease and wound healing. [unreadable] [unreadable]